Facioscapulohumeral muscular dystrophy (FSHD) is an adult onset myopathy with epigenetic changes that most commonly occur as a consequence of reduction in the number of 3.3 kb D4Z4 units arrayed on chromosome 4 to less than 11 units. The contraction-induced epigenetic profile results in transcription of the normally repressed DUX4 retrogene and produces myopathic changes that manifest as muscle weakness when contractions occur on arrays with permissive D4Z4 haplotypes. Five percent of FSHD-affected individuals develop FHSD despite having D4Z4 array lengths greater than the 10 unit threshold so FSHD occurring by this mechanism has been called FSHD2 or contraction-independent FSHD. D4Z4 arrays of individuals with FSHD2 show epigenetic de-repression similar to that seen by the more common mechanism but chromatin changes extend to similar arrays on chromosome 10, and the other chromosome 4 allele suggesting that contraction-independent array-derepression may occur through the activity of genes involved in epigenetic modification of macrosatellite repeats. We performed exome sequencing of FSHD2-affected individuals and their unaffected family members to identify one of these loci. Rare variants present in 61% of FSHD2-affected individuals segregated independently of permissive haplotypes on chromosome 4 and only resulted in FSHD when a permissive haplotype and gene variant were present in the same individual. Consistent with our hypothesis, reduction of protein levels from this gene results in D4Z4 array de-repression and DUX4 expression in normal human myoblasts from unaffected individuals. Here we propose to determine the context and timing of these epigenetic changes at D4Z4 macrosatellite repeats, and assess the effect of genes with similar activities on DUX4 transcription in individuals with either FSHD1 or FSHD2. Using this approach we hope to explain disease phenomena such as non-penetrance, variable expressivity, and asymmetric distributions of muscle weakness as well as identify gene targets for possible pharmacological intervention.